The present invention provides an efficient process for the preparation of an enantiomerically enriched beta amino acid derivative of structural formula I:
having the (R)- or (S)-configuration at the stereogenic center marked with an *; wherein    Z is OR2, SR2, or NR2R3;    R1 is C1-8 alkyl, aryl, heteroaryl, aryl-C1-2 alkyl, or heteroaryl-C1-2 alkyl;    R2 and R3 are each independently hydrogen, C1-8 alkyl, aryl, or aryl-C1-2 alkyl; or R2 and R3 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclic ring system optionally containing an additional heteroatom selected from O, S, and NC1-4 alkyl, said heterocyclic ring system being optionally fused with a 5- to 6-membered saturated or aromatic carbocyclic ring system or a 5- to 6-membered saturated or aromatic heterocyclic ring system containing one to two heteroatoms selected from O, S, and NC1-4 alkyl, said fused ring system being unsubstituted or substituted with one to two substituents independently selected from hydroxy, amino, fluoro, C1-4 alkyl, C1-4 alkoxy, and trifluoromethyl.
The process of the present invention relates to a method for the preparation of chiral beta amino acid derivatives of structural formula I in an efficient enantioselective fashion via transition metal-catalyzed asymmetric hydrogenation of a prochiral enamine of structural formula II:
wherein the amino group is unprotected, in the presence of a chiral ferrocenyl diphosphine ligand.
Methods for asymmetrically reducing enamine carbon-carbon double bonds (C═C—N) using chiral ferrocenyl diphosphines as ligands complexed to a rhodium or iridium precursor have been described in the patent literature (See U.S. Pat. No. 5,563,309 issued Oct. 8, 1996 to Ciba-Geigy Corp. and the related family of patents and patent applications). A related approach to N-acylated beta amino acids using a rhodium Me-DuPHOS catalytic complex has also published (U.S. 2002/0128509 published on Sep. 12, 2002 assigned to Degussa AG). The following publications also describe the asymmetric hydrogenation of N-acylated beta-amino acrylic acids with rhodium metal precursors complexed to a chiral phosphine ligand: (1) T. Hayashi, et al., Bull. Chem. Soc. Japan, 53: 1136-1151 (1980); (2) G. Zhu et al., J. Org. Chem., 64: 6907-6910 (1999); and (3) W. D. Lubell, et al., Tetrahedron: Asymmetry, 2: 543-554 (1991). In these publications all the examples provided have the amino group in the beta amino acrylic acid derivative substrate protected as an acetamide derivative. The requirement for amine protection introduces two additional chemical steps into the sequence, namely protection and deprotection, and the synthesis of the protected substrate may also be difficult. The process of the present invention circumvents the need for protecting the primary amino group in the substrate for the asymmetric hydrogenation reaction and proceeds with excellent reactivity and enantioselectivity.